CA2197466A1 - Compositions - Google Patents

Abstract

There is provided a contrast medium composition comprising a physiologically tolerable manganese compound, an uptake promoter and a physiologically tolerable carrier or excipient, having a manganese concentration of at least 0.3mM or being in a dosage unit form containing at least 300 .mu.mol manganese, wherein the uptake promoter comprises a physiologically tolerable reducing compound containing an .alpha.-hydroxy ketone group, a physiologically tolerable acid containing .alpha.- and/or .beta.-hydroxy or amino groups, or a salt thereof, and/or vitamin D. Such compositions are particularly suitable for imaging of the liver.

Description

wo g6ios867 2 l 9 7 4 6 ~ PC'T/GB951019(i9 COMPOS ITIONS

The present invention relates to 1 ,_~v~ nts in ~ and relating to magnetic resonance imaging (MRI) and in particular to compositions for use as or in the preparation of MRI contrast media for imaging of the stomach, intestine, liver, bile duct and gall bladder.
MRI is now well established as a medical diagnostic tool. The ability of the technique to generate high quality images and to differentiate between soft tissues without requiring the patient to be exposed to ioni~ing rA~;Rt;o" has contributed to this success.
Although MRI can be performed without using added contrast media, it has been found that substances which affect the nuclear spin reequilibration of the nuclei ~hereinafter the ~'imaging nuclei" - generally water protons in body fluids and tissues) responsible for the magnetic resonance ~MR) signals from which the images are generated may be used to enhance image contrast and, accordingly, in recent years, many such materials have been suggested as MRI contrast agents.
The P"h~nrP~ contrast obtained with the use of contrast agents enables particular organs or tissues to be vi~UAl i7P~ more clearly by increasing or by decreasing the signal level of the particular organ or tissue relative to that of its ~ULlU""~; rg~ . Contrast agents raising the signal level of the target site relative to that of its ~LLV"~; ngC are termed ~positive~ contrast agents whilst those lowering the signal level relative to ~uLL~ dings are termed ~negative~ contrast agents.
The majority of materials now being proposed as MRI
contrast media achieve a contrast effect because they contain paramagnetic, superparamagnetic or ferromagnetic species.

WOg6~8G7 PCT/GB95/01~ -21~746~ 2 -For ferromagnetic and superparamagnetic contra6t agents, which are negative MRI contrast agents, the enhanced image contrast derives primarily from the rG~nctinn in the spin reequilibration parameter known as T2 or as the spin-spin relaxation time, a reduction arising from the effect on the imaging nuclei of the fields generated by the feLL~ ~"etic or SUpeLl _ ?t~ C particles.
PaI gn~tic contrast agents on the other hand may be either positive or negative MRI contrast agents. The effect of paramagnetic substances on magnetic resonance signal intensities is ~opPn~Pnt on many factors, the most important of which are the rnrr~n~ration of the paL. 3n~tl C gubstance at the imaged site, the nature of the paL -_ ~tic substance itself and the pul~e sequence and magnetic field strength used in the imaging routine.
Generally, however, paramagnetic contrast agents are positive MRI contrast agents at low cnnr~ntrations where their T1 lowering effect dominates and negative MRI
contrast agents at higher cnnrrntrations where their T2 lowering effect is d ~n~nt, In either event, the relaxation time r~dnrt;~n results from the effect on the imaging nuclei of the magnetic fields g~n~r~tod by the paramagnetic centres.
The use o~ tic, f~ gn~tic and superp~rnm-~n~t;r materials as MRI contrast agents has been widely advocated and broad ranges of suitable materials have been suggested in the literature.
An example of a physiologically tolerable paramagnetic material known for use as an MRI contrast agent is r~ J~ e ion, which may conveniently be used in the form of its salts or rh~l~t~s. Indeed, even at very low i.v. dosages (about S-10 ~mol/kg bodyweight) manganese has been found to be particularly effective as a contrast agent for imaging of the liver.
~ owever m~ng~n~se~ when administered intravenously as a contrast agent, may be teratogenic at clinical 096/05~7 ~1~ 7 4 6 ~ '.il569 dosages. Administered intravenously, ~-ng~nPRe is also known to interfere with the normal functioning of the heart by replacement of calcium in the calcium pump of the heart.
In order to reduce the direct effect on the heart, ~ oral administration has been proposed. This ensures passage of the contrast agent through the liver before going to the heart.
Oral administration of MnCl2 as a liver imaging MR
contrast agent has been proposed and orally administered MnCl2 has not been found to be teratogenic. ~owever, the absorption of MnCl2 through the gut is poor, and as a result the dosage required for clinical efficacy is of the order of 100-1000 ~mol/kg bodyweight. In the event of damage to the gut resulting in increased uptake, such a high dosage level still has the potential for causing undesired adverse effects, eg. cardiac effects.
We have now surprisingly found that gastrointestinal tract m=ng=nPRe contrast agents suitable for imaging of the liver may be produced by the incorporation of an uptake promoter capable of PnhAnr;ng m-ng~nP~e transport across the ' anes of the g.i.
tract.
C ,_' 'R which have been found to be suitable for use as uptake promoters include reducing compounds cnntA;n;ng an ~-hydroxy ketone group (-C(OH)-CO-), acids crntA;n;ng ~- and/or ~-hydroxy or amino groups, as well as vitamin D.
Thus, viewed from one aspect the present invention provides a contrast medium composition comprising a physiologically tolerable ~-ng~n~Re c~ o~d, an uptake promoter and a physiologically tolerable carrier or ~r; piPnt, having a m-ng=nP.~e concentration of at least 0.3mM or being in a dosage unit form rrntA;n;ng at least 300 ~mol r-ng~nPRe, wherein the uptake promoter comprises a physiologically tolerable reducing compound rrnt=;n;ng an ~-hydroxy ketone group, a phys;olsg;rAlly W096/0s8~7 i~ sS~ -21 97466 4 _ tolerable acid r~n~;n;ng ~- and/or ~-hydroxy or amino groups, or a salt thereof, and/or vitamin D.
As used herein, the expression "acid containing ~-and/or ~-hydroxy or amino groups" is intended to include aromatic acids c~n~ining ortho-hydroxy or ortho-amino group~.
The contrast medium composition according to the invention may comprise a r-ng~n~se compound together with a mixture of several uptake promoters.
The ~J~l~p~ce c , -~, which prefera~ly is soluble in gastrointestinal fluid may for examp~e be a chelate or a salt, or may be a mixture of different salts and/or chelates. Particularly preferred are metal rhPl~t~ and salts in which the r~ng~n~e is present as MnlII) rather than Mn(III) since the former has a higher magnetic moment and thus is more effective as an MR contrast agent.
The reducing nature of the uptake promoter is important since normal uptake of ~ Re by the gut tends to favour Mn(II) rather than Mn(III).
Pre~erred compositions ~co~;ng to the invention are those in which the reducing _luulld ~urther ~nt~ i n~ an oxygen atom in a heterocyclic ring structure.
Particularly pre~erred as an uptake promoter in the compositions of the invention is ascorbic acid which has been found to increase the uptake of manganese in the liver about 5-fold compared with oral administration of MnCl2 alone. This surprising increase is demonstrated in Figure 2 of the accompanying drawings. Moreover ascorbic acid (vitamin C) is particularly preferred as an uptake promoter since it is cheap, readily available and particularly well tolerated by the body.
Yet more particularly preferred compositions in accordance with the invention are those in which the uptake promoter is kojic acid. The dramatic increase in the uptake of ~-ng~ e in the liver following ~ W09610s867 2 1 q7466 PCT/GB95/01969 administration of MnCl2 ~ kojic acid can be seen from Figure 5 of the Acc ying drawings.
R~Ample~ of acids which have been found to be particularly effective as uptake promoters in the compositions of the invention include carboxylic acids, e.g. gluconic and salicyclic acid. The effect of the addition of salicylic acid to MnClz on MRI ~nhAn~ ~ of the liver can be seen in Figure 8 of the accompanying drawings. ~- and ~- amino acids have also been found to be useful as uptake promoters, in particular ~-amino acids, e.g. glycine, valine, glutamine, aspartic acid, glutamic acid, lysine, arginine, cysteine and methionine, especially arginine, lysine and aspartic acid. The effect of addition of various ~-amino acids to MnCl2 on MRI ~nhAn~ of the liver is shown in accu,..~a.1ying Figure 9.
Other preferred compositions in accordance with the invention are those which comprise vitamin ~ as an uptake promoter.
Using the compositions of the invention, the liver can be effectively MR imaged with a significant reduction in the dosage of --ng~n~Re otherwise required.
Thus, for example, a 50~ ~nhAn~ of the liver can be obtained by oral administration of lOO ~mol r ng~n~se/kg body weight and l mmol ascorbic acid/kg. Such a dosage results in the same degree of ~nhAns t of the liver as 5 ~mol Mn(II)~kg body weight (MnCl2, i.v.) or as 500 ~mol Mn(II)/kg body weight (MnCl2, p.o.).
Figure l hereto demonstrates the effect of p.o.
administration of MnCl2 and ascorbic acid on MR liver ~nh~n~ nt compared with p.o. administration of MnCl2 alone.
Increase in the ratio of ascorbic acid to MnCl2 results in an increase in the ~nh~n, t effect obtained. This dose-L~u-1se relationch; r can be seen from Figure 2 hereto.
The gradual increase in ~nhAn~-~nt of the liver WO 96/115867 ~ '~ 9 ~ ~ 6 r ~ I/I~D7~ S69 with time following administration oE a composition in accordance with the invention enables the dynamics of uptake of the contrast agent by the liver to he monitored (see for example Figure 2). This is of particular importance in enabling identification of areas of healthy tissue and areas of possible tumor growth.
In the compositions Accor~;ng to the invention, the preferred molar ratio of manganese to uptake promoter is from 1:0.2 to 1:50, eg. 1:1 to 1:20, especially 1:3 to 1:6, particular preferably about 1:5.
The uptake promoter may if desired be present in whole or in part as the counterion to the r~ng~n~e ions. Thus in one c~~n~; t the composition of the invention comprises as both ~-J~Pqe - ~ and uptake promoter a --ng~n~qe salt of a reducing cnnt~;n;ng an ~-hydroxy ketone group or a ~ngAneqe salt of an acid ~nnt~;n;ng ~- and/or ~- hydroxy or amino group~, eg. r ngAnPse ~II) ascorbate or r-ng~n~e salicylate.
m e compositions according to the invention may be used to achieve a 60-called ~doublc contrast effectn by increasing the signal level from the liver whilst at the same time decreasing that ~rom the surrounding tissues, in particular ~rom the gut. Such an ef~ect enableq yet further ~nh~n, ' of the liver.
A double contrast effect and margin definition can be achieved with the compositions of the invention since the resulting manganese ion cnnn~ntration within the g.i. tract will generally be such as to create a signal ~u~p~ssing effect there. In this case, to avoid image artefacts resulting from pockets of the gut being contrast agent free, it is desirable to incorporate in the compcsitions a viscosity ~nh~nn;ng agent and desirably also an osmoactive agent. Examples of suitable viscosity Pnh~rr~rs and osmoactive agents are described in W0 91/01147 and W0 91/01148.

~ W096105867 2 1 ~ 7 4 b b PCTIGBsS/01969 In a particularly preferred embodiment, the compositions of the invention may be used in ~ ~;n~tion with a second contrast agent having either a positive or negative contrast effect. Preferably the compositions of the invention are used in cn~;n~tion with a second contrast agent having an opposing contrast effect. This results in a "double contrast effect" enabling visllRl;c~t;on and margin definition of the liver to be particularly PnhRn~P~.
As ~;nnpd above, paramagnetic materials such as ~-ng~nP~e ions may act as either positive or negative MRI contrast agents ~rPn~;ng upon a number of factors, including the ronrPntration of the ions at the imaging site and the magnetic field strength used in the imaging procedure. At the cnncpntrations of m~ng~n~se rnnt~ lated for use in the compositions of the invention, the ~-ng~n~se-cnnt~;n;ng contrast agent will, in general, function as a positive contrast agent. The second contrast agent is therefore conveniently a negative contrast agent and may be any negative MRI
contrast agent suitable for oral administration.
However, as indicated above, any MR contrast agent, negative or positive, may be used.
3xamples of negative MRI contrast agents for use in cn~inAt;nn with the compositions of the invention include known ferrn~-gnptic and superparamagnetic species, such as for example magnetic iron oxide particles either free or enclosed within or bound to a non-magnetic matrix material such as a polysaccharide eg. LUMIREM and 5nlrhnn~tPd polystyrene eg. ABDOSCAN~.
Further ~l~c of contrast agents for use in combination with the compositions of the invention include Gd and Dy ions bound to a polymeric matrix, for example LUMIREM or GADOLITE (~ nl; n; alumina silicate oral suspension).
When using the compositions of the invention to achieve a double contrast effect, it is particularly W096/0586~ 9 7 ~b 6 - 8 - PCT~GR9~0196s preferable to incorporate a viscosity ~rh~n~; ng agent which attains its full visco~ity ~nhAnr;ng effect only after administration of the contrast medium. The contrast medium is thus able to be inyested in a relatively tolerable form while yet developing the desired viscosity at or during passage towards the site which is to be imaged.
The compositions of the invention are particularly suited to use, if required after dispersion in aqueous media, for imaging of the liver. For such a purpose the compositions may be administered into the gastrointestinal tract orally, rectally or via a stomach t.ube.
Thus, viewed from a further aspect the present invention provides a method of generating a magnetic resonance image of a human or non-humanl preferably r~ n, ani~al body which methoa comprises administering into the gastrn;nt~Rt;n~l tract of a said body a contrast medium comprising a physiologically tolerable r-n~n~e ~- _ ' and a physiologically tolerable reducing ol,nfl ~nnt~;n;ng an a-hydroxy ketone group or a physiologically tolerable aoid nt~;n;ng a- and/or ~- hydroxy or amino groups, or a salt thereof, and~or vitamin D, and generati~g a magnetic r~nn~nce image of the liver and the gastro-intestinal tract. of said body.
Viewed from a yet further aspect the invention also provides a method of generating a magnetic resonance image of a human or non-human animal body, which method comprises administering into the gastrointestinal tràct of a said body an effective amount of a composition comprising: (a~ a first contrast agent comprising a physiologically tolerable r-rg~n~Re compound, a physiologically tolerable reducing ~ fl ~nnt~i n; ng an a-hydroxy ketone group or a physiologically tol~r~hle acid cnnt~;n;ng a- and~or ~- hydroxy or amino groups, or a salt thereof, and/or vitamin D, preferably having a ~ W09610s867 2 1 ~7 4~6 r~ . r~ol~g g ~ngAn~Se cnnrPntration of at least 0.3mM or being in a dosage unit form cnnt~;n;ng at least 300 ~mol ~-ngAnPse, together with (b~ a second contrast agent and generating a magnetic resonance image of the liver and abdomen of said body.
It is possible to fu~ te the contrast medium immediately or shortly prior to administration by mixing the uptake promoter with the ~-ng~npse species. Thus, in a further aspect the invention also provides an MRI
contrast agent kit comprising in a first rnntA;n~r a physiologically tolerable ~-ngAnpse ~o~ u~.d, and in a second r~ntA;nPr a physiologically tolerable reducing compound containing an ~-hydroxy ketone group or a physiologically tolerable acid cnntA;n;ng ~- and/or ~-hydroxy or amino groups, or a salt thereof, and/or vitamin D.
Viewed from a further aspect the invention also provides an MRI contrast agent kit comprising in a first rnnt~;nPr a first contrast agent comprising a physiologically tolerable ~-ngAnPre c~ronn~, a physiologically tolerable reducing c _u-~d Cnnt~;n;ng an ~-hydroxy ketone group or a physiologically tolerable acid nnntAin;ng ~- and/or ~- hydroxy or amino groups, or a salt thereof, and/or vitamin D, preferably having a ~-n~AnP~e ~nn~Pntr~tinn of at least 0.3mM or being in a dosage unit form cnntAin;"s at least 300 ~mol ~-ng~n~se, and in a second rnntAinPr a second contrast agent comprising a particulate ferromagnetic or superparamagnetic material or Gd or Dy ions bound to a polymeric matrix.
The contrast agent compositions of the invention may of course include components other than the uptake promoter, the ~-ngAnP~e compound, the viscosity ~nh~nc;ng and osmoactive agents, for example convPn~;nn~l ph~rr~relltical fo~ tion aids such as wetting agents, buffers, disintegrants, binders, fillers, flavouring agents and liquid carrier media such W096/058G7 ~ 1 97466 PCT/GB95~1969 ~

as sterile water, water/ethanol etc.
For oral administration, the pH of the composition is preferably in the acid range, eg. 2 to 7 and while the uptake promoter may itself serve to yield a composition with this pH, buffers or pH adjusting agents may be used.
The contrast media may be fnr~ t~a, in conventional pharmaceutical administration forms, such as tablets, capsules, powders, solutions, dispersions, syrups, suppositories etc.
The preferred dosage of the composition according to the present invention will vary according to a number of factors, such as the administration route, the age, weight and species of the subject and the particular uptake promoter used. Conveniently, the dosage of ~~ng~nrRP will be in the range of fr ~ 5 to 500 ~mol/kg bodyweight, preferably from 5 to 150 ~mol/kg bodyweight, more preferably from 10 to 100 ~mol/kg bodyweight, while the dosage of the uptake promoter will be in the range of from 5 ~mol to 1 mmol/kg bodyweight, preferably from 25 ~mol to 0.5 ~mol/kg bodyweight.
Preferred : ~ a; tR 0~ the invention will now be described by reference to the following non-1;m;t;ng ~xamples and the ~r~ ~nying drawings, in which:
Figure 1 is a graph illustrating the effect of p.o.
administration of different Mn2~ salts on liver hAnCr~-~t;
Figure 2 is a graph illustrating the effect of p.o.
administration of MnC12 + ascorbic acid on liver ,- at varying conr~ntrations of ascorbic acid;
and Figure 3 is a graph illustrating the effect of p.o.
administration of different doses of MnCl2 rontAin;ng 0.1 mmol/kg ascorbic acid on liver ~nh~nr~~~nt Figure 4 is a graph illustrating the effect of the ~ a.; t; nn of ascorbic acid or ascorbic acid-palmitate to MnCl2 on ~nh~rc t of the liver.

~ W0961058C7 ~1 97~66 PCTlGBg5101969 Figure 5 is a graph illustrating the effect of the addition of ascorbic acid or kojic acid to MnCl2 on ~nh~nl L of the liver.
Figure 6 is a graph illustrating the results of a phar~ro~;nPtic study to determine the variation in ~ c~ncPn~ation of Mn(II) in the blood following administration of various Mn(II)-c~nt~;n;ng compositions. ~ ~

Figure 7 is a graph comparing the effect on liver ~nh~nr - of i.v. administration of Mn DPDP (S-095) with that of p.o. administration of MnCl2 + ascorbic acid.
Figure 8 is a graph illustrating the effect of the addition of ascorbic and salicylic acids to MnCl2 on liver Pnh~rr Figure 9 is a graph illustrating the effect of the addition of different amino acids to MnCl2 on liver Pnh~nr , Figure 10 illustrates transversal Tl-weighted (SE
57/13; 2.4 T) liver images from a control rat and from three rats 2 hours after oral administration of 200 ~mol/kg MnCl2 + 1000 ~mol/kg ascorbate. The signal intensity of the liver is substantially increased after gavage administration of Mn2t and ascorbate.
Figure 11 illustrates coronal Tl-weighted (SE
90/17; 2.4 T) liver images from two rats 2 hours after oral administration of 200 ~mol/kg MnCl2 + 1000 ~mol/kg ascorbate. The signal intensity in the gastrointestinal lumen is reduced a_ter administration of Mn2+.
Figures 12 and 13 are graphs illustrating the effect of the addition of ABDOSCAN~ to Mn-ascorbate on the Pnh~nc ~ of the liver.
Figure 14 illustrates transversal Tl-weighted (SE
57/13; 2.4 T) liver images from a control rat and from three rats 2 hours after oral administration of 200 ~mol/kg MnCl2 + 1000 ~mol/kg ascorbate + ~3DOSCAN~ (21 W096/0s867 21 ~74G6 - 12 - PcT/~B9~/01~69 ~

~mol/kg Pe). The addition of A~3DOSCAN did not influence the signal intensity of the liver.
Figure 15 illustrates coronal Tl-weig~hted (SE
9O/17; 2.4 T~ liver images from a control rat and from a rat 2 hours after oral administration of 200 ~mol/kg MnCl2 + 1000 ~mol/kg ascorbate + ~BDOSCAN~ (21 ~mol/kg Fe). The signal intensity in the gastrointestinal lumen is markedly reduced after co-administration of Mn2+ and AB~OSCAN .
For the measurement of the curves of Figures l to 9 the following materials were used:

Fi~-re 1 Mn - A ccorbate MnCl2 x ZH,O 6.48 g Ascor~ic acid 35.2 g Water ~ 1000 ml Mn-gluconAte Mn-gluconate 19.2 g Water ~ lOOO ml Mn-citrate Mncl2 x 2H2O 6.48 g Na3-citrate x 2H2O 23.5 g Water ~1 1000 ml Ficnlre 2 ~ 12 MnCl2 x 2~2O 6.48 g Water ad 1000 ml Mn~l2 + D.l mmnl /kg ~ccnrhic Arid MnCl2 x 2X2O 6.48 g ~rorhjc acid 3.52 g . .

~ W096/05867 ~l 9746b PCT/GB95lolg69 Water ~d 1000 ml Mn~12 + 0.4 rm~l/kg ascorbic acid MnCl2 x 2H20 6.48 g Ascorbic acid 14.1 g Water ~ 1000 ml Mn~l ~ + 1.0 1 /kg ~corbic acid MnCl2 x 2H20 ~ 6.48 g Ascorbic acid ~ 35.2 g Water ~d 1000 ml Figure 3 MnCl2 (0.2 l/kg) + ~qcorbic acid MnC12 x 2H20 6.48 g Ascorbic acid 3.52 g Water ~d 1000 ml Mn~l 2 (~ . 5 l/kg) + aqc~rhic acid M~Cl2 x 2H20 16.2 g Ascorbic acid 3.52 g Water ~d 1000 ml Mn~ 2 (2.0 l/kg) + ~r~rh; c acid MnCl2 x 2H20 64.8 g Ascorbic acid 3.52 g nater ad 1000 ml Fiq~re 4 ~2 MnCl2 x 2H20 13.0 g Water ad 1000 ml Mn~12 + ~r~rhic acid ~ m;tate (0.4 ~l/kg) L-ascorbic acid 6-palmitate 66.4 g W096/~867 ~l 9 74 6 ~ PCT~GB9~01969 Polyethylene glycol 300 ~ 1000 ml Fi~re 5 Mn~l2 + k~Jlc arid tO.4 1/kq) MnCl2 X 2~0 6.48 g Koj ic acid 11. 4 g Water ~ 1000 ml Fi~lre 8 Mn~l2 (0. 2 l/kg) MnCl2 X 2~20 6.4 8 g Water ~ 1000 ml ~l2 ~0.2 l/kg) + ~rnrhic acid (Q.4 l/k,g~
MnCl2 X 2H~0 6.48 g Ascorbic acid 14.1 g Water ~ 1000 ml Mnrl2 (0.2 l/kg) + 5al;cyllc aci~ (0.4 r~ k,q) MnCl2 x 2~206.48 g Salicyclic acid sodium sal~~2. 8 g Water d 1000 Fi~lre 9 Mn~l 2 (0 .2 ~mn3 /kg) MnCl2 X 2H2~ 6.48 g Water ad 1000 ml Mn~l 2 (0 .2 l/k~) + ~ccnrh;c acid ~o .4 ~mnl ~kg~
MnCl2 X 2H2~ 6.48 g Ascorbic acid 14.1 g Water ~ lO00 ml ~ W096/05867 ~ 19 7466 PCTIGB95/01969 Mnrl2 (0.2 ~l/kg) + glycin~ (0.4 l/kg) MnCl2 x 2H20 6.48 g Glycine 7.76 g ~ Water ~1000 ml ~ Mnrl2 (0.2 ~l/kg) + v~l;nP (0.4 ~l/kg) MnCl2 x 2H20 6.48 g Valine 9.36 g Water ~1000 ml Mn~la (0.2 l/kg) + glut~m;n~ (0 4 l/kg) MnCl2 x 2H20 6.48 g Glutamine 11.7 g Water ~1000 ml MnGl2 (0.2 -l/kg) + ~ rtic acid ~0.4 l/kg) MnCl2 x 2H20 6.48 g Aspartic acid 13 .8 g Water ~ 1000 ml Mn~l2 (0.2 l~kg) + glutAmic ~id (0.4 l/kg) MnCl2 x 2H206. 48 g Glutamic acid monosodium salt monohydrate15.0 g Water ~1 1000 ml Mn~l2 (0.2 l/kg) + lys;n~ (0 4 l/kg) MnCl2 x 2H20 6.48 g Lysine monohydrochloride 14.6 g Water ~ 1000 ml Mn~l2 (0.2 l/kg) + ~rginin~ (0 4 l/kg) MnCl2 x 2H20 6.48 g Arginine monohydrochloride 16.9 g Water ~ 1000 ml W096~05X67 2 ~ 9 74 6 6 PCI~/GB95/019b9 ~

MnC-2 ~0.2 l/kg) + c~ste;n~ lo 4 l/kgl MnCl2 x 2~2O 6.48 g Cysteine monohydrochloride monohydrate 14.0 g Water ad 1000 ml MnCl2 10.2 l/k~) + ~th;on;n~ (0.4 ~l/kgi MnC12 x 2~2O 6.48 g MPth; ~n; ne 11.9 g Water ad 1000 ml Por the mea~uL. of the curves of Figures lZ and 13 the following materials were used:

MnCl2 x 2~2O 0.567 g Ascorbic acid 3.08 g A}3DOSCAN0 23.4 mg Fe (one dose-package~
Water ~d 200 ml r le 1 Or~l C ~~itinn MnCl2 x 2~20 6.48 g A~corbic acid 35.2 g Water ~ 1000 ml The ~-ng~n~e chloride and ascorbic acid are dissolved in sterile deionised water. The dose for a 70 kg adult human would be 350 ml, taken orally.

E le 2 Or~l f O~itinn MlICl2 X 2~20 6 . 48 g Kojic acid 11.4 g W096/05867 2l 9 7 4 6 b PCT/GB9S/01969 Water ~ 1000 ml The m~ng~nGse chloride and kojic acid are dissolved in ~ sterile deionised water. The dose for a 70 kg adult human would be 350 ml, taken orally.

E le 3 OrAl Co~osition MnCl2 x 2~20 13.0 g Water ~ 1000 ml B.
L-ascorbic acid 6-palmitate66.4 g ~ Polyethylene glycol 300 ~1000 ml The dose for a 70 kg adult human would be 175 ml of A
and 175 ml of B, taken orally.

~m~le 4 Orsl Cnm~osit;nn MnCl2 x 2H20 0.567 g Ascorbic acid 3.08 g ABDOSCAN0 23.4 mg Fe Water ad 200 ml The doRe for a 70 kg adult human would be 4 x 200 ml, taken orally.

746~
W096/05~6~ pcrlGB9s~l96 ~le 5 Oral t~m,rosition - Mnt~l2 (0.2 r-~-,1/kq) + vi~;~m;n ~ 0 . 4 r~ kq~

A.
MnCl2 x 2E~20 13 . O g Water ~ lOOO ml Vitamin D 30 . O g Polyethylene glycol 300 ~51 1000 ml

Claims (23)

Claims

1. A contrast medium composition comprising a physiologically tolerable manganese compound, an uptake promoter and a physiologically tolerable carrier or excipient, having a manganese concentration of at least 0.3mM or being in a dosage unit form containing at least 300 µmol manganese, wherein the uptake promoter comprises a physiologically tolerable reducing compound containing an .alpha.-hydroxy ketone group, a physiologically tolerable acid containing .alpha.- and/or .beta.-hydroxy or amino groups, or a salt thereof, and/or vitamin D, and wherein the molar ratio of manganese to uptake promoter is at least 1:2.

2. A composition as claimed in claim 1 wherein the uptake promoter comprises one or more of the compounds defined in claim 1.

3. A composition as claimed in claim 1 or claim 2 wherein the manganese compound is a chelate or a salt in which the manganese is present as Mn(II).

4. A composition as claimed in any one of claims 1 to 3 wherein the reducing compound further contains an oxygen atom in a heterocyclic ring structure.

5. A composition as claimed in any one of claims 1 to 4 wherein the uptake promoter is ascorbic acid.

6. A composition as claimed in any one of claims 1 to 4 wherein the uptake promoter is kojic acid.

7. A composition as claimed in any one of claims 1 to 3 wherein the acid is gluconic or salicylic acid.

8. A composition as claimed in any one of claims 1 to 3 wherein the acid is an .alpha.- or .beta.-amino acid.

9. A composition as claimed in claim 8 wherein the acid is glycine, valine, glutamine, aspartic acid, glutamic acid, lysine, arginine, cysteine or methionine.

10. A composition as claimed in claim 8 or claim 9 further comprising vitamin D.

11. A composition as claimed in any one of claims 1 to 3 wherein the uptake promoter is vitamin D.

12. A composition as claimed in any preceding claim wherein the uptake promoter is present in whole or in part as the counterion to the manganese ions.

13. Use of a physiologically tolerable manganese compound together with an uptake promoter in the manufacture of a diagnostic agent for use in a method of image generation practised on the human or non-human animal body, wherein said uptake promoter comprises a physiologically tolerable reducing compound containing an .alpha.-hydroxy ketone group or a physiologically tolerable acid containing .alpha.- and/or .beta.- hydroxy or amino groups, or a salt thereof, and/or vitamin D, and wherein the molar ratio of manganese to uptake promoter is from 1:0.2 to 1:50.

14. A method of generating a magnetic resonance image of a human or non-human animal body which method comprises administering into the gastrointestinal tract of a said body a contrast medium comprising a physiologically tolerable manganese compound and a physiologically tolerable reducing compound containing an .alpha.-hydroxy ketone group or a physiologically tolerable acid containing .alpha.- and/or .beta.- hydroxy or amino groups, or a salt thereof, and/or vitamin D, wherein the molar ratio of manganese to uptake promoter is from 1:0.2 to 1:50, and generating a magnetic resonance image of the liver and abdomen of said body.

15. An MRI contrast agent kit comprising in a first container a physiologically tolerable manganese compound, and in a second container an uptake promoter comprising a physiologically tolerable reducing compound containing an .alpha.-hydroxy ketone group, or a physiologically tolerable acid containing .alpha.- and/or .beta.-hydroxy or amino groups, or a salt thereof, and/or vitamin D, and wherein said manganese compound and uptake promoter are present in an amount sufficient to provide a molar ratio of manganese compound to uptake promoter of from 1:0.2 to 1:50.

16. A contrast medium composition comprising:
(a) a composition comprising a physiologically tolerable manganese compound, an uptake promoter and a physiologically tolerable carrier or excipient, having a manganese concentration of at least 0.3mM or being in a dosage unit form containing at least 300 µmol manganese, wherein the uptake promoter comprises a physiologically tolerable reducing compound containing an .alpha.-hydroxy ketone group, a physiologically tolerable acid containing .alpha.- and/or .beta.-hydroxy or amino groups, or a salt thereof, and/or vitamin D, together with b) a second contrast agent.

17. A composition as claimed in claim 16 wherein the second contrast agent has an opposing contrast effect to said first contrast agent.

18. A composition as claimed in claim 16 or claim 17 wherein the second contrast agent has a negative contrast effect.

19. A composition as claimed in claim 16 or claim 17 wherein the second contrast agent has a positive contrast effect.

20. A composition as claimed in claim 16 or claim 17 wherein the second contrast agent comprises a particulate ferromagnetic or superparamagnetic material.

21. A composition as claimed in claim 16 or claim 17 wherein the second contrast agent comprises Gd or Dy ions bound to a polymeric matrix.

22. A method of generating a magnetic resonance image of a human or non-human animal body, which method comprises administering into the gastrointestinal tract of a said body an effective amount of a composition as defined in claim 16 and generating a magnetic resonance image of the liver and abdomen of said body.

23. An MRI contrast agent kit comprising in a first container a first contrast agent comprising a physiologically tolerable manganese compound, a physiologically tolerable reducing compound containing an .alpha.-hydroxy ketone group or a physiologically tolerable acid containing .alpha.- and/or .beta.- hydroxy or amino groups, or a salt thereof, and/or vitamin D, and in a second container a second contrast agent as defined in claim 20 or claim 21.